CRY2 and FBXL3 Cooperatively Degrade c-MYC

Anne Laure Huber, Stephanie J. Papp, Alanna B. Chan, Emma Henriksson, Sabine D. Jordan, Anna Kriebs, Madelena Nguyen, Martina Wallace, Zhizhong Li, Christian M. Metallo, Katja A. Lamia

Research output: Contribution to journalArticlepeer-review

Abstract

For many years, a connection between circadian clocks and cancer has been postulated. Here we describe an unexpected function for the circadian repressor CRY2 as a component of an FBXL3-containing E3 ligase that recruits T58-phosphorylated c-MYC for ubiquitylation. c-MYC is a critical regulator of cell proliferation; T58 is central in a phosphodegron long recognized as a hotspot for mutation in cancer. This site is also targeted by FBXW7, although the full machinery responsible for its turnover has remained obscure. CRY1 cannot substitute for CRY2 in promoting c-MYC degradation. Their unique functions may explain prior conflicting reports that have fueled uncertainty about the relationship between clocks and cancer. We demonstrate that c-MYC is a target of CRY2-dependent protein turnover, suggesting a molecular mechanism for circadian control of cell growth and a new paradigm for circadian protein degradation.

Original languageEnglish
Pages (from-to)774-789
Number of pages16
JournalMolecular Cell
Volume64
Issue number4
DOIs
Publication statusPublished - 2016 Nov 17

Subject classification (UKÄ)

  • Cell and Molecular Biology

Free keywords

  • circadian clock
  • circadian rhythm
  • CRY2
  • cryptochrome
  • FBXL3
  • MYC
  • ubiquitin

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